Process for producing 3,3,3-trifluoro-2-hydroxypropionic acid or its derivative

ABSTRACT

The invention relates to a process for producing 3,3,3-trifluoro-2-hydroxypropionic acid. This process includes the step of (a) bringing a 1,1-dihalogeno-3,3,3-trifluoroacetone into contact with a basic aqueous solution. The obtained 3,3,3-trifluoro-2-hydroxypropionic acid may be reacted with a C 1 -C 6  lower alcohol under an acidic condition, thereby producing a 3,3,3-trifluoro-2-hydroxypropionate. This propionate may be reacted with a hydride reducing agent (e.g., sodium borohydride), thereby producing 3,3,3-trifluoro-2-hydroxypropanol. These products (i.e., 3,3,3-trifluoro-2-hydroxypropionic acid and its derivatives) are important intermediates for medicines and liquid crystals.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to processes for producing3,3,3-trifluoro-2-hydroxypropionic acid and its derivatives, which areuseful intermediates for medicines and liquid crystals.

[0002] There are known the following first to fourth processes forproducing 3,3,3-trifluoro-2-hydroxypropionic acid, which is representedby the formula 2.

[0003] In the first process, it is derived from3,3,3-trifluoro-2-hydroxypropanol or 3,3,3-trifluoropropene-1,2-oxide(see Synlett, 7, pp. 507-508 (1994); and Japanese Patent ApplicationPublications 5-078277 and 5-078278).

[0004] In the second process, it is derived from trifluoropyruvate (seeChem. Ber., 125(12), pp. 2795-2802 (1992)).

[0005] In the third process, it is derived from trifluoroacetaldehyde(see Japanese Patent Application Publication 3-148249).

[0006] In the fourth process, it is derived from hexafluoroisopropanol(see Nippon Kagaku Kaishi No. 9, pp. 1576-1586 (1989)).

[0007] Other processes for producing 3,3,3-trifluoro-2-hydroxypropionicacid are disclosed in Japanese Patent Application Publications2002-080429 and 2001-226316; Organic Letters, 3(3), pp. 457-459 (2001);Tetrahedron Letters, 41(23), pp. 4603-4607 (2000), and TetrahedronLetters, 41(22), pp. 4507-4512 (2000).

[0008] Although it is possible to obtain3,3,3-trifluoro-2-hydroxypropionic acid with a relatively high yield bythe above conventional processes, the raw materials (i.e.,trifluoromethyl-containing compounds) used in these processes have veryhigh prices. Therefore, these processes are not suitable forindustrially producing 3,3,3-trifluoro-2-hydroxypropionic acid.

[0009] The following reaction scheme is taught in WO 02/00601corresponding to European Patent Application EP 1300391 A1; WO 00/55113corresponding to U.S. patent application Publication 2002/0026081 A1;Huaxue Gongcheng (Xilan, China), 28(4), pp. 44-45, 51 (2000); JapanesePatent Application Publication 10-139724; WO 98/07687 corresponding toU.S. Pat. No. 6,020518; J. Indian Chem. Soc., 66(4), pp. 239-240 (1989);J. Antibiot., 40(11), pp. 1555-1562 (1987); Tetrahedron, 37(17), pp.3061-3065 (1981); Yukagaku, 28(7), pp. 501-502 (1979); and German PatentApplication Publication 2648300 corresponding to U.S. Pat. No.4,052,460.

[0010] Furthermore, it is disclosed in Chem. Ber., 125(12), pp.2795-2802 (1992) that 3,3,3-trifluoro-2-hydroxypropionic acid alkylester is protected at its hydroxyl group (bonded to the second carbon)with a THP (tetrahydropyranyl) group, and then its alkoxycarbonyl group(—COOR) is reduced to a hydroxymethyl group (—CH₂OH) using lithiumaluminum hydride. Then, it is necessary to conduct a deprotection toproduce 3,3,3-trifluoro-2-hydroxypropanol. Thus, the process of thispublication is cumbersome for industrial production.

[0011] Japanese Patent Application Publication 2000-063306 disclosesthat 1,1-dichloro-3,3,3-trifluoroacetone is hydrolyzed in the presenceof disodium hydrogenphosphate to trifluoropropanetetraol. It is furtherdisclosed in this publication that the hydrolysis is conducted at a pHof from 2 to 9.

[0012] Japanese Patent Application Publication 5-70406 discloses aprocess for producing a β, β,β-trifluorolactic acid ester by reactingβ,β,β-trifluorolactic acid with an alcohol (having a carbon atom numberof at least 3) in the presence of a catalyst.

SUMMARY OF THE INVENTION

[0013] It is an object of the present invention to provide a process forefficiently producing 3,3,3-trifluoro-2-hydroxypropionic acid or itsderivative(s), which are useful intermediates for medicines and liquidcrystals.

[0014] According to the present invention, there is provided a processfor producing 3,3,3-trifluoro-2-hydroxypropionic acid represented by theformula 2. This process includes the step of (a) bringing a1,1-dihalogeno-3,3,3-trifluoroacetone represented by the formula 1 intocontact with a basic aqueous solution (for example, having a pH of 12 orhigher),

[0015] wherein X is Cl, Br or I.

[0016] The above raw material, 1,1-dihalogeno-3,3,3-trifluoroacetone, isindustrially available with a low price.

[0017] It is possible to convert 3,3,3-trifluoro-2-hydroxypropionic acidinto 3,3,3-trifluoro-2-hydroxypropanol represented by the formula 4almost quantitatively, by a process including the steps of:

[0018] (b) reacting the 3,3,3-trifluoro-2-hydroxypropionic acid, whichhas been obtained by the above step (a), with a lower alcoholrepresented by the formula 5, under an acidic condition, therebyproducing a 3,3,3-trifluoro-2-hydroxypropionate represented by theformula 3; and

[0019] (c) reacting the 3,3,3-trifluoro-2-hydroxypropionate with ahydride reducing agent, thereby producing the3,3,3-trifluoro-2-hydroxypropanol,

[0020] wherein R is a C₁-C₆ lower alkyl group.

[0021] It is possible by the above step (c) to efficiently reduce thealkoxycarbonyl group (—CO₂R) into the hydroxymethyl group (—CH₂OH) usinga hydride reducing agent (e.g., sodium borohydride), without necessityof protecting the hydroxyl group (bonded to the second carbon) of theraw material, 3,3,3-trifluoro-2-hydroxypropionate and without necessityof the following deprotection. Thus, it is possible to easily obtain3,3,3-trifluoro-2-hydroxypropanol with high yield and less load inindustrial production.

[0022] The above-mentioned exemplary hydride reducing agent, sodiumborohydride, is low in price and easy for handling. Thus, this sodiumborohydride is considerably superior in safety and economy to lithiumaluminum hydride.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] In general, strongly basic condition (for example, having a pH of12 or higher) has been considered as being not preferable fortrifluoromethyl-containing compounds due to the tendency ofdecomposition of the trifluoromethyl group under such condition. Theinventors, however, tried to bring the above1,1-dihalogeno-3,3,3-trifluoroacetone into contact with a basic aqueoussolution. With this, we unexpectedly found that the decomposition of thetrifluoromethyl group does actually not occur and thereby the targetproduct, 3,3,3-trifluoro-2-hydroxypropionic acid, can be obtained withhigh yield.

[0024] The above-mentioned steps (a), (b) and (c) for producing3,3,3-trifluoro-2-hydroxypropanol can be shown by the following reactionscheme. As stated above, a target product of the present invention,3,3,3-trifluoro-2-hydroxypropionic acid, can be obtained by the step(a).

[0025] The step (a) is described in detail as follows. It is possible toefficiently produce 1,1-dichloro-3,3,3-trifluoroacetone, which can bethe raw material of the step (a), by a process of Japanese PatentApplication Publication 10-287609, 10-330308, 11-001451 or 2000-063306,in which pentachloroacetone is fluorinated in a gas or liquid phase into1,1-dichloro-3,3,3-trifluoroacetone. Similarly, it is possible to obtain1,1-dibromo-3,3,3-trifluoroacetone and 1,1-diiodo-3,3,3-trifluoroacetoneby fluorinating pentabromoacetone and pentaiodoacetone, respectively.

[0026] Although the obtained 1,1-dihalogeno-3,3,3-trifluoroacetoneitself can be used as the raw material of the step (a), it can be usedin the step (a) as a hydrate since it mixes freely with water. Thishydrate is easy for handling and can have, for example, the followingformula 6:

[0027] wherein X is defined as in the formula 1, and n is a numbergreater than 0. Furthermore, it is optional to mix1,1-dihalogeno-3,3,3-trifluoroacetone with a solvent (e.g., alcohol)other than water to form a solvate. This solvate can also be used as theraw material of the step (a). Thus,1,1-dihalogeno-3,3,3-trifluoroacetone of the formula 1 to be used in thestep (a) is defined in the present specification as including itshydrate and solvate.

[0028] In case that 1,1-dihalogeno-3,3,3-trifluoroacetone is used as itshydrate in the step (a), the amount of water relative to that of1,1-dihalogeno-3,3,3-trifluoroacetone for preparing the hydrate is notparticularly limited. This water is in an amount of preferably 1-10moles, more preferably 1-5 moles, relative to 1 mol of1,1-dihalogeno-3,3,3-trifluoroacetone. A typical exemplary hydrate is atrihydrate in which 3 moles of water coexist with 1 mole of1,1-dihalogeno-3,3,3-trifluoroacetone. This trihydrate is represented bythe formula 6, in which n equals to 2. Using too much amount of waterfor preparing the hydrate is not problematic to the reactivity, butlowers the productivity. Therefore, it is not preferable.

[0029] The type of a base for preparing the basic aqueous solution ofthe step (a) is not particularly limited. It is preferably an inorganicbase (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide,sodium carbonate, and potassium carbonate), in terms of reactivity andof preventing the production of impurities that are difficult to beseparated from the target product. It is optional to combine a pluralityof inorganic bases for preparing the basic aqueous solution. Of theabove examples, sodium hydroxide and potassium hydroxide are preferable,since they are high in basicity and since pH of the resulting basicaqueous solution can easily be controlled. In particular, sodiumhydroxide is more preferable.

[0030] In the step (a), the base concentration of the basic aqueoussolution is not particularly limited and can suitably be set in view ofsolubility of the inorganic base in water. The base concentration ispreferably 1-50 wt %, more preferably 1-40 wt %, of the basic aqueoussolution.

[0031] The base of the basic aqueous solution may be in an amount of atleast 2 equivalents, preferably 2-20 equivalents, more preferably 2-10equivalents, relative to 1 equivalent of the compound of the formula 1.

[0032] The pH of the basic aqueous solution during the step (a) ispreferably 12 or higher, more preferably 12-14, still more preferably13-14. Although it may have a pH within these ranges by using the basein the above-described amount, it is preferable to measure pH of thereaction mixture at a suitable interval by using a known measure (e.g.,pH test paper). In fact, pH of the reaction mixture (solution) graduallylowers as the reaction of the step (a) proceeds, since a halogenatedhydracid (e.g., hydrochloric acid) is generated by the reaction. If thepH becomes too low, conversion and selectivity of the reaction becomeextremely low. Therefore, it is preferable in the reaction of the step(a) to measure pH of the reaction mixture at a suitable interval and toadd the base to the reaction mixture when the measured pH is lower than12.

[0033] It is optional to use a reaction solvent in the step (a). Itsnonlimitative examples include (1) aliphatic hydrocarbons such asn-pentane, n-hexane, cyclohexane, and n-heptane; (2).aromatichydrocarbons such as benzene, toluene, xylene, and mesitylene; (3)halogenated hydrocarbons such as methylene chloride, chloroform, and1,2-dichloroethane; (4) ethers such as diethyl ether, tetrahydrofuran,t-butyl methyl ether, and dioxane; (5) esters such as ethyl acetate andn-butyl acetate; (6) nitriles such as acetonitrile and propionitrile;(7) alcohols such as methanol, ethanol, n-propanol, and i-propanol; and(8) water. Of these, preferable examples are diethyl ether,tetrahydrofuran, t-butyl methyl ether, methanol, ethanol, i-propanol,and water. In particular, tetrahydrofuran, methanol, ethanol, and waterare more preferable. It is possible to use a single solvent or a mixtureof at least two of these. It is possible to conduct the reaction withoutusing any reaction solvent.

[0034] The reaction temperature of the step (a) may be from −10° C. to+100° C., preferably −10° C. to +80° C., more preferably 0° C. to +60°C.

[0035] The way of adding the substrate is not particularly limited inthe step (a). It is, however, preferable to add the substrate graduallyin order to stably maintain the temperature of the reaction mixture,since the reaction of the step (a) generates a relatively strong heat.For example, the compound of the formula 1 may be added dropwise to thebasic aqueous solution, or the basic aqueous solution may be addeddropwise to the compound of the formula 1. In this case, the droppingrate may suitably be adjusted such that the inside temperature of thereactor does not become significantly higher than the outside settemperature. For example, it may be adjusted that the temperaturedifference between the inside and the outside is 10° C. or less.

[0036] In the reaction of the step (a), it is optional to stir thereaction mixture for about 1-3 hrs for ageing, after gradually addingthe substrate. A stirring for a very long time (e.g., 24 hr or longer)may not further improve yield. Such stirring may lower the efficiency ofthe reaction and thus may not be preferable.

[0037] Post-treatment of the step (a) is not particularly limited. Atthe end of the reaction of the step (a), the target product,3,3,3-trifluoro-2-hydroxypropionic acid represented by the formula 2, ispresent as a salt formed by a reaction of3,3,3-trifluoro-2-hydroxypropionic acid with the base in an excessiveamount. Thus, it is easily possible to add an inorganic acid to areaction liquid obtained by the step (a) to convert this salt into3,3,3-trifluoro-2-hydroxypropionic acid, followed by extraction with anorganic solvent to isolate 3,3,3-trifluoro-2-hydroxypropionic acid. Theinorganic acid may be selected from hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid. Of these, hydrochloric acid andsulfuric acid are preferable, and hydrochloric acid is more preferable.

[0038] The above-mentioned extraction solvent may be selected from (1)aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane, andn-heptane; (2) aromatic hydrocarbons such as benzene, toluene, xylene,and mesitylene; (3) halogenated hydrocarbons such as methylene chloride,chloroform, and 1,2-dichloroethane; (4) ethers such as diethyl ether,tetrahydrofuran, t-butyl methyl ether, and dioxane; and (5) esters suchas ethyl acetate and n-butyl acetate. Of these, preferable examples aretoluene, t-butyl methyl ether, and ethyl acetate. In particular, t-butylmethyl ether and ethyl acetate are more preferable. It is possible touse a single solvent or a mixture of at least two of these.

[0039] In the step (a), the resulting extracted solution may besubjected to washing with water and brine, drying, and concentration,thereby obtaining a crude product. According to need, the crude productmay be subjected to purification (e.g., the use of activated carbon,rectification, recrystallization, and column chromatography), therebyobtaining 3,3,3-trifluoro-2-hydroxypropionic acid of the formula 2 withhigh purity.

[0040] The step (b) is described in detail as follows. The step (b) canbe conducted by reacting 3,3,3-trifluoro-2-hydroxypropionic acid, whichhas been obtained by the step (a), with a lower alcohol represented bythe formula 5, in the presence of an acid catalyst, thereby producing3,3,3-trifluoro-2-hydroxypropionate represented by the formula 3. Thestep (b) may be conducted in accordance with a conventionalesterification.

[0041] The lower alcohol represented by the formula 5 may be selectedfrom methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol,i-propanol, 2-butanol, and cyclohexanol.

[0042] The lower alcohol of the formula 5 may be in an amount of 1equivalent or greater, relative to 1 equivalent of3,3,3-trifluoro-2-hydroxypropionic acid. In particular, it is possibleto use an excessive amount of the lower alcohol as a reaction solvent.

[0043] The acid catalyst for conducting the step (b) may be selectedfrom organic acids (e.g., benzenesulfonic acid, p-toluenesulfonic acid,10-camphorsulfonic acid) and inorganic acids (e.g., hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, zinc chloride, andtitanium tetrachloride). Of these, p-toluenesulfonic acid and sulfuricacid are preferable. In particular, sulfuric acid is more preferable.

[0044] The acid catalyst may be in a catalytic amount relative to thatof 3,3,3-trifluoro-2-hydroxypropionic acid. It is preferably 0.001-1equivalent, more preferably 0.005-0.5 equivalents, relative to oneequivalent of 3,3,3-trifluoro-2-hydroxypropionic acid.

[0045] In the step (b), water is produced as a by-product as thereaction proceeds. It is possible to accelerate the reaction by removingsuch water from the reaction system. Thus, the reaction of the step (b)can be conducted in the presence of a dehydrating agent such as zeolite(e.g., molecular sieve), phosphorus pentoxide, anhydrous sodium sulfate,and anhydrous magnesium sulfate, to remove water during the step (b). Incase that the lower alcohol of the formula 5 is immiscible with water,has a specific gravity less than that of water, and forms an azeotropicmixture with water, it is possible to remove water from a Dean-Starktrap, while the reaction is conducted under reflux with or withoutreaction solvent (e.g., benzene and toluene).

[0046] The reaction temperature of the step (b) may be from 0° C. to+200° C., preferably from 0° C. to +150° C., more preferably from 0° C.to +100° C. The reaction time for conducting the step (b) may be 48 hror shorter and may vary depending on the reaction conditions. Therefore,it is preferable to terminate the reaction after confirming that the rawmaterial was almost completely consumed, by checking the progress of thereaction by a suitable analytical technique (e.g., gas chromatography,thin layer chromatography, and NMR).

[0047] Post-treatment of the step (b) is not particularly limited. It ispossible to easily obtain a crude product by subjecting a reactionmixture itself at the end of the reaction to distillation. This crudeproduct can be used in the subsequent step (c). Alternatively, accordingto need, the crude product may be subjected to purification (e.g., theuse of activated carbon, rectification, recrystallization, and columnchromatography), thereby obtaining 3,3,3-trifluoro-2-hydroxypropionateof the formula 3 with very high purity.

[0048] The step (c) is described in detail as follows. As stated above,the step (c) can be conducted by reacting3,3,3-trifluoro-2-hydroxypropionate of the formula 3 with a hydridereducing agent, thereby producing 3,3,3-trifluoro-2-hydroxypropanol ofthe formula 4.

[0049] The hydride reducing agent may be selected from (1) aluminumhydrides such as (i-Bu)₂AlH, (i-Bu)₃Al, [2,6-(t-Bu)₂-4-MePh]Al(i-Bu)₂,LiAlH₄, LiAlH(OMe)₃, LiAlH(O-t-Bu)₃ and NaAlH₂(OCH₂CH₂OCH₃)₂; (2) boronhydrides such as diborane, BH₃-THF, BH₃-SMe₂, BH₃-NMe₃, 9-BBN, NaBH₄,NaBH₄-CeCl₃, LiBH₄, Zn(BH₄)₂, Ca(BH₄)₂, Li(n-Bu)BH₃, NaBH(OMe)₃,NaBH(OAc)3, NaBH₃CN, Et₄NBH₄, Me₄NBH(OAc)₃, (n-Bu)₄NBH₃CN,(n-Bu)₄NBH(OAc)₃, Li(sec-Bu)₃BH, K(sec-Bu)₃BH, LiSia₃BH, KSia₃BH,LiEt₃BH, KPh₃BH, (Ph₃P)₂CuBH₄, ThxBH₂, Sia₂BH, catechol borane, IpcBH₂and Ipc₂BH; and (3) silicon hydrides such as Et₃SiH, PhMe₂SiH, Ph₂SiH₂and PhSiH₃-Mo(CO)₆, where Bu represents butyl group, Ph representsphenyl group, Me represents methyl group, THF representstetrahydrofuran, 9-BBN represents 9-borabicyclo[3,3,1]nonane, Acrepresents acetyl group, Sia represents siamyl group, Et representsethyl group, Thx represents thexyl group, and Ipc representsisopinocampheyl group. Among these, LiAlH₄, diborane, NaBH₄ and LiBH₄are preferable. NaBH₄ is particularly more preferable, since it is lowin price and can easily be used in a large amount. These hydridereducing agents can also be used in the presence of various inorganicsalts.

[0050] The hydride reducing agent may be in an amount of 0.25equivalents or greater, preferably 0.25-10 equivalents, more preferably0.25-7.0 equivalents, relative to one equivalent of 3,3,3-trifluoro-2-hydroxypropionate.

[0051] It is preferable to conduct the reaction of the step (c) insolvent. Its nonlimitative examples include (1) aliphatic hydrocarbonssuch as n-pentane, n-hexane, cyclohexane, and n-heptane; (2) aromatichydrocarbons such as benzene, toluene, xylene, and mesitylene; (3)halogenated hydrocarbons such as methylene chloride, chloroform, and1,2-dichloroethane; (4) ethers such as diethyl ether, tetrahydrofuran,t-butyl methyl ether, and dioxane; (5) esters such as ethyl acetate andn-butyl acetate; (6) nitriles such as acetonitrile and propionitrile;(7) alcohols such as methanol, ethanol, n-propanol, and i-propanol; and(8) carboxylic acids such as acetic acid, propionic acid, and butyricacid. Of these, preferable examples are diethyl ether, tetrahydrofuran,t-butyl methyl ether, methanol, ethanol, and i-propanol. In particular,tetrahydrofuran, methanol, ethanol, and i-propanol are more preferable.It is possible to use a single solvent or a mixture of at least two ofthese.

[0052] The reaction temperature of the step (c) may be from −100° C. to+100° C., preferably −80° C. to +80° C., more preferably −60° C. to +60°C. The reaction time for conducting the step (c) may be 24 hr or shorterand may vary depending on the reaction conditions. Therefore, it ispreferable to terminate the reaction after confirming that the rawmaterial was almost completely consumed, by checking the progress of thereaction by a suitable analytical technique (e.g., gas chromatography,thin layer chromatography, and NMR).

[0053] In a reaction mixture at the end of the reaction of the step (c),3,3,3-trifluoro-2-hydroxypropanol of the formula 4 is stably present asa five-membered cyclic compound represented by the formula 7.

[0054] Thus, the target product is still mostly in the form of the abovefive-membered cyclic compound, even if the reaction mixture obtained bythe step (c) is extracted with organic solvent.

[0055] It is, however, possible to easily hydrolyze the five-memberedcyclic compound by treating the same with an inorganic acid (e.g.,hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphorus acid)or fluoride ions, thereby isolate 3,3,3-trifluoro-2-hydroxypropanol. Infact, it is possible to add an inorganic acid to a reaction product(containing the five-membered cyclic compound) of the step (c), followedby heating at a constant temperature, thereby isolating the targetproduct (i.e., 3,3,3-trifluoro-2-hydroxypropanol) with high yield.Although the way of this isolation is not particularly limited, it caneffectively be conducted by dissolving the reaction product of the step(c) in methanol, then by adding a sulfuric acid aqueous solution, andthen by heating under reflux.

[0056] It is possible to conduct a solvent extraction with an organicsolvent to collect 3,3,3-trifluoro-2-hydroxypropanol, which has beenisolated by the above-mentioned acid treatment. Examples of the organicextraction solvent include (1) aliphatic hydrocarbons such as n-pentane,n-hexane, cyclohexane, and n-heptane; (2) aromatic hydrocarbons such asbenzene, toluene, xylene, and mesitylene; (3) halogenated hydrocarbonssuch as methylene chloride, chloroform, and 1,2-dichloroethane; (4)ethers such as diethyl ether, tetrahydrofuran, t-butyl methyl ether, anddioxane; and (5) esters such as ethyl acetate and n-butyl acetate. Ofthese, preferable examples are toluene, diethyl ether, t-butyl methylether, and ethyl acetate. In particular, diethyl ether and ethyl acetateare more preferable. It is possible to use a single solvent or a mixtureof at least two of these.

[0057] In the step (c), the resulting extracted solution may besubjected to washing with water and brine, drying, and concentration,thereby obtaining a crude product. According to need, the crude productmay be subjected to purification (e.g., the use of activated carbon,rectification, recrystallization, and column chromatography), therebyobtaining 3,3,3-trifluoro-2-hydroxypropanol with high purity.

[0058] The following nonlimitative Examples are illustrative of thepresent invention.

EXAMPLE 1

[0059] The step (a) of the present invention was conducted as follows.At first, 235 g (1 mol, 1 eq.) of 1,1-dichloro-3,3,3-trifluoroacetonetrihydrate were added dropwise by spending 2.5 hr to 533 g (4 mol, 4eq.) of 30 wt % sodium hydroxide aqueous solution under cooling withice, while the internal temperature of the reaction liquid wasmaintained at 25° C. or lower, followed by stirring for 1 hr. Afterthat, 197 g (2 mol, 2 eq.) of 37 wt % hydrochloric acid aqueous solutionwere added dropwise to the reaction liquid under cooling with ice, whilethe internal temperature of the reaction liquid was maintained at 25° C.or lower. Then, 180 ml of water were added under room temperature todissolve the precipitated sodium chloride. The resulting solution wasextracted two times with 500 ml of ethyl acetate. Then, the combinedorganic layer was washed one time with 500 ml of saturated brine,concentrated and dried under vacuum, thereby obtaining 163 g of a crudeproduct of 3,3,3-trifluoro-2-hydroxypropionic acid. This crude productwas found by ¹H-NMR to contain 81.5 wt % of3,3,3-trifluoro-2-hydroxypropionic acid (yield: 92%). This crude productwas used in the following step (b) of Example 2 without conducting afurther purification. The obtained 3,3,3-trifluoro-2-hydroxypropionicacid was found to have the following characteristics.

[0060]¹H-NMR (standard substance: TMS; solvent: CD₃OD), δ ppm: 4.53 (q,7.6 Hz, 1H); ¹⁹F-NMR (standard substance: C₆F₆, solvent: CD₃OD), δ ppm:87.75 (d, 7.6 Hz).

EXAMPLE 2

[0061] The step (b) of the present invention was conducted as follows.At first, 2.84 g of the crude product obtained by Example 1 (containing16.07 mmol (1.00 eq.) of 3,3,3-trifluoro-2-hydroxypropionic acid) and19.6 mg (0.20 mmol, 0.01 eq.) of 98% sulfuric acid were added to 20 mlof ethanol, followed by stirring for 43 hr with heating under reflux.The resulting reaction liquid itself was subjected to a vacuumdistillation (52° C./3,500 Pa), thereby obtaining 1.87 g of white,needle-like crystals of ethyl 3,3,3-trifluoro-2-hydroxypropionate of thefollowing formula 8. The yield was 68%. The obtained crude product (thewhite, needle-like crystals) was used in the following step (c) ofExample 3 without conducting a further purification.

[0062] Ethyl 3,3,3-trifluoro-2-hydroxypropionate was found to have thefollowing characteristics.

[0063]¹H-NMR (standard substance: TMS; solvent: CDCl₃), δ ppm: 1.35 (t,7.6 Hz, 3H), 3.42 (br, 1H), 4.30-4.47 (m, 2H), 4.47 (q, 7.6 Hz, 1H);¹⁹F-NMR (standard substance: C₆F₆, solvent: CDCl₃), δ ppm: 85.58 (d, 7.6Hz).

EXAMPLE 3

[0064] The step (c) of the present invention was conducted as follows.At first, 1.87 g (10.87 mmol, 1.00 eq.) of the white, needle-likecrystals of ethyl 3,3,3-trifluoro-2-hydroxypropionate, which had beenproduced in Example 2, were dissolved in 20 ml of ethanol. Then, 0.41 g(10.84 mmol, 1.00 eq.) of sodium borohydride were added under coolingwith ice, followed by stirring at room temperature for 12 hr. Then, thereaction was terminated by adding 10 ml of 10 wt % hydrochloric acidaqueous solution, followed by adding 5 ml of water to dissolveundissolved substances. The resulting liquid was extracted two timeswith 20 ml of diethyl ether. The combined organic layer was washed onetime with 10 ml of saturated brine. The resulting organic layer wasdried with anhydrous sodium sulfate, concentrated and dried undervacuum, thereby obtaining an organic matter residue. This organic matterresidue was found by ¹H-NMR to be formed mostly of a five-memberedcyclic compound (represented by the following formula 9), obtained by areaction of 3,3,3-trifluoro-2-hydroxypropanol with boron.

[0065] Then, to the total amount of the obtained organic matter residue10 ml of methanol and 10 ml of 10 wt % sulfuric acid aqueous solutionwere added, followed by stirring for 24 hr with heating under reflux.After the reaction, methanol was distilled away, and the organic matterresidue was dissolved by adding 20 ml of water. The obtained solutionwas extracted two times with 20 ml of diethyl ether. The combinedorganic layer was dried with anhydrous sodium sulfate, concentrated,dried under vacuum, and distilled under vacuum (62° C./1000 Pa), therebyobtaining 1.12 g of 3,3,3-trifluoro-2-hydroxypropanol as a purifieddistillate. The yield was 79%. The obtained3,3,3-trifluoro-2-hydroxypropanol was found to have the followingcharacteristics.

[0066]¹H-NMR (standard substance: TMS; solvent: CDCl₃), δ ppm: 2.02 (br,1H), 3.06 (br, 1H), 3.83-3.92 (m, 2H), 4.03-4.13 (m, 1H); ¹⁹F-NMR(standard substance: C₆F₆, solvent: CDCl₃), δ ppm: 84.05 (d, 7.6 Hz).

[0067] The entire contents of Japanese Patent Application No.2002-179554 (filed Jun. 20, 2002), which is a basic Japanese applicationof the present application, are incorporated herein by reference.

What is claimed is:
 1. A process for producing3,3,3-trifluoro-2-hydroxypropionic acid represented by the formula 2,the process comprising the step of (a) bringing a1,1-dihalogeno-3,3,3-trifluoroacetone represented by the formula 1 intocontact with a basic aqueous solution,

wherein X is Cl, Br or I.
 2. A process according to claim 1, wherein thebasic aqueous solution has a pH higher than
 12. 3. A process accordingto claim 1, wherein the basic aqueous solution has a pH of from 12 to14.
 4. A process according to claim 1, wherein the basic aqueoussolution has a pH of from 13 to
 14. 5. A process according to claim 1,wherein, when pH of the basic aqueous solution becomes lower than 12during the step (a), a base is added to the basic aqueous solution suchthat the basic aqueous solution has a pH higher than
 12. 6. A processaccording to claim 1, wherein the basic aqueous solution comprises aninorganic base selected from the group consisting of sodium hydroxide,potassium hydroxide, lithium hydroxide, sodium carbonate, potassiumcarbonate, and mixtures of these.
 7. A process according to claim 6,wherein the inorganic base is selected from the group consisting ofsodium hydroxide, potassium hydroxide, and mixtures of these.
 8. Aprocess according to claim 7, wherein the inorganic base is sodiumhydroxide.
 9. A process according to claim 1, wherein the basic aqueoussolution comprises 1-50 wt % of an inorganic base.
 10. A processaccording to claim 1, wherein the basic aqueous solution comprises 1-40wt % of an inorganic base.
 11. A process according to claim 1, whereinthe basic aqueous solution comprises a base in an amount of at least 2equivalents, relative to one equivalent of the1,1-dihalogeno-3,3,3-trifluoroacetone.
 12. A process according to claim1, wherein the basic aqueous solution comprises a base in an amount offrom 2 to 20 equivalents, relative to one equivalent of the1,1-dihalogeno-3,3,3-trifluoroacetone.
 13. A process according to claim1, wherein the basic aqueous solution comprises a base in an amount offrom 2 to 10 equivalents, relative to one equivalent of the1,1-dihalogeno-3,3,3-trifluoroacetone.
 14. A process according to claim1, wherein the step (a) is conducted at a temperature of from −10° C. to+100° C.
 15. A process according to claim 1, wherein the step (a) isconducted at a temperature of from −10° C. to +80° C.
 16. A processaccording to claim 1, wherein the step (a) is conducted at a temperatureof from 0° C. to +60° C.
 17. A process according to claim 1, wherein thestep (a) is conducted at about room temperature or lower by cooling areaction liquid of the step (a).
 18. A process according to claim 1,wherein the step (a) is conducted by adding the1,1-dihalogeno-3,3,3-trifluoroacetone dropwise to the basic aqueoussolution.
 19. A process according to claim 1, wherein the step (a) isconducted by adding the basic aqueous solution dropwise to the1,1-dihalogeno-3,3,3-trifluoroacetone.
 20. A process according to claim1, further comprising the steps of: (b) adding an inorganic acid to areaction liquid obtained by the step (a) to convert a salt of the3,3,3-trifluoro-2-hydroxypropionic acid into the3,3,3-trifluoro-2-hydroxypropionic acid; and (c) extracting a product ofthe step (b) with an organic solvent to isolate the3,3,3-trifluoro-2-hydroxypropionic acid.
 21. A process according toclaim 20, wherein the inorganic acid of the step (b) is hydrochloricacid.
 22. A process according to claim 20, wherein the organic solventof the step (c) is selected from the group consisting of toluene,t-butyl methyl ether, ethyl acetate, and mixtures of these.
 23. Aprocess for producing 3,3,3-trifluoro-2-hydroxypropanol represented bythe formula 4, the process comprising reacting a3,3,3-trifluoro-2-hydroxypropionate, represented by the formula 3, witha hydride reducing agent,

wherein R is a C₁-C₆ lower alkyl group.
 24. A process according to claim23, wherein the hydride reducing agent comprises sodium borohydride. 25.A process for producing 3,3,3-trifluoro-2-hydroxypropanol represented bythe formula 4, the process comprising the steps of: (a) reacting3,3,3-trifluoro-2-hydroxypropionic acid represented by the formula 2,with a lower alcohol represented by the formula 5, under an acidiccondition, thereby producing a 3,3,3-trifluoro-2-hydroxypropionaterepresented by the formula 3; and (b) reacting the3,3,3-trifluoro-2-hydroxypropionate with a hydride reducing agent,thereby producing the 3,3,3-trifluoro-2-hydroxypropanol,

wherein R is a C₁-C₆ lower alkyl group.
 26. A process for producing3,3,3-trifluoro-2-hydroxypropanol represented by the formula 4, theprocess comprising the steps of: (a) bringing a1,1-dihalogeno-3,3,3-trifluoroacetone represented by the formula 1 intocontact with a basic aqueous solution, thereby producing3,3,3-trifluoro-2-hydroxypropionic acid represented by the formula 2;(b) reacting the 3,3,3-trifluoro-2-hydroxypropionic acid with a loweralcohol represented by the formula 5, under an acidic condition, therebyproducing a 3,3,3-trifluoro-2-hydroxypropionate represented by theformula 3; and (c) reacting the 3,3,3-trifluoro-2-hydroxypropionate witha hydride reducing agent, thereby producing the3,3,3-trifluoro-2-hydroxypropanol,

wherein X is Cl, Br or I; and R is a C₁-C₆ lower alkyl group.